Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth.

Katharina B Kuentzel,Dagmar Kolb,Nemanja Vujić,Melanie Korbelius,Ivan Bradić,Dagmar Kratky,Martin Gauster,Silvia Rainer,Alena Akhmetshina

doi:10.3390/ijms221910416

Katharina B Kuentzel, Dagmar Kolb + Show 7 more

Open Access

https://doi.org/10.3390/ijms221910416

Copy DOI

Abstract

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.

Highlights

The mouse placenta, which we isolated on day 19 of pregnancy, is composed of three different layers, with the maternally derived decidua separated from the labyrinth by the junctional zone (Figure 1A)
Biochemical lipid estimation revealed that the mouse placenta contains more cholesterol, mainly free cholesterol (FC), than TG (Figure 1B)
Western blot analysis of tissue lysates confirmed the abundance of hormone-sensitive lipase (HSL) and lysosomal acid lipase (LAL) protein in the WT

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cholesterol and fatty acids (FA) are essential lipids for membrane biosynthesis and organ development. Two sources maintain an adequate supply of cholesterol: the body’s own (endogenous) production and exogenous intake from the diet in the postnatal period. Regardless of its source, cholesterol is transported in the bloodstream in form of lipoproteins. Unesterified free cholesterol (FC) is an important structural component of cell membranes to ensure membrane fluidity, a precursor for steroid hormones, bile acids, and vitamin D, and is involved in cell signaling processes. An excessive amount of FC is toxic and may disrupt cell membrane fluidity and integrity. Excess cholesterol is stored in the cell in the inert form of cholesteryl esters (CE). CE are hydrolyzed in two distinct cellular compartments at different pH values by the action of specific enzymes

Methods

Results

Conclusion